Cholinesterase is needed for the proper functioning of the nervous systems of humans. If the amount of cholinesterase is reduced below a critical level, nerve impulses to the muscles can no longer be controlled, resulting in serious consequences and even death. The term cholinesterase is generally referred to one of the two enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE or BuChE). Acetylcholinesterase (AChE), also known as RBC cholinesterase, erythrocyte cholinesterase, or (most formally) acetylcholine acetylhydrolase, is found primarily in the blood and neural synapses. Butyrylcholinesterase (BuChE), also known as pseudocholinesterase, plasma cholinesterase, or (most formally) acylcholine acylhydrolase, is found primarily in the liver. Both of these enzymes catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.
Acetylcholinesterase (AChE) is a tetrameric protein which catalyzes the hydrolysis of the neurotransmitter acetylcholine (a chemical released by nerves that activates muscle contractions) and helps to maintain proper transmission of impulses between nerve cells and between nerve cells and muscles. A variety of neurological and neuromuscular disorders or diseases involve a diminution of cholinergic activity. Often the most effective treatments for such disorders or diseases involve use of a cholinesterase inhibitor which inhibits the breakdown of acetylcholine. A cholinesterase inhibitor or anticholinesterase is a chemical or a ligand that inhibits a cholinesterase enzyme from breaking down acetylcholine, so increasing both the level and duration of action of the neurotransmitter acetylcholine. Acetylcholinesterase inhibitors have been used clinically in the treatment of Alzheimer's disease or Alzheimer type dementia, Huntington's disease, Pick's disease, ataxia, myasthenia gravis (a degenerative neuromuscular disorder) and glaucoma.
Alzheimer's disease or Alzheimer type dementia (also called as Senile Dementia of the Alzheimer Type) is a progressive illness that kills nerve cells and destroys nerve connections in the brain. The disease is marked by mental changes resulting from damage in the brain tissue. Because these changes cannot be visualized until autopsy, diagnosis for the disease is based on symptoms that patients have. Symptoms include gradual loss of awareness, memory, and judgment as well as mood and behavioral disturbances. While the exact cause of this disease is still unknown, researchers have found several factors that may contribute to the development of the disease, including an inflammatory response, genetic factors, and environmental influences.
Prevalence of Alzheimer's disease across the world is unknown. However, recent reports suggest that about 4.5 million Americans have Alzheimer's disease. It is estimated that by the year 2050 this number will be greater than 13 million because the baby boomers will by that year be over the age of 65. Alzheimer's disease is the leading cause of dementia (the loss of healthy mental function) and the eighth leading cause of death in the United States. The lifespan of an Alzheimer's disease victim is generally reduced, although a person may live anywhere from 3 to 20 years after diagnosis.
Alzheimer's disease is not reversible and currently there is no cure for this disease. The pharmacological treatments currently available are mainly aimed at alleviating or improving symptoms of the disease. Cholinesterase inhibitors are commonly prescribed and are the only agents approved by the FDA for the treatment because they have been shown to minimize and stabilize the symptoms of Alzheimer's disease. The FDA approved cholinesterase inhibitors are donepezil (Aricept®), tacrine (Cognex®), rivastigmine (Exelon®), and galantamine (Reminyl®). Clinical trials show that these drugs can stabilize or improve cognition, global assessment scores, mood and behavior in people with Alzheimer's disease. In recent years, Donepezil (Sugimoto et al. U.S. Pat. Nos. 4,895,841 and 5,100,901; Pathi et al. WO 2007077443; Parthasaradhi et al. WO 2005003092; Dubey et al. WO 2005076749; Gutman et al. WO 200009483; Sugimoto et al. J Med Chem 1995, 38, 4821) has been used as a first-line therapy for the treatment of Alzheimer's disease.
However, all the AChE inhibitors currently in clinical use including donepezil have notable limitations. They exhibit substantial interpatient variability in pharmacokinetics and have significant interactions with other drugs. An important reason for interpatient variability and interactions with other drugs (drug-drug interactions) involves genetically determined differences in the metabolism of these drugs. All AChE inhibitors currently in clinical use undergo significant hepatic metabolism via cytochrome P450 isoenzymes 3A4, including 2D6 and 1A2 isoenzymes except rivastigmine. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions (Buffum et al. Geriatric Nursing 2005, 26, 74-78). There are significant polymorphisms in patients for CYP isoenzymes CYP2D6 and CYP1A2 (Shah, R. R. Phil. Trans. R. Soc. B. 2005, 360, 1617-1638), and this polymorphism has been shown to substantially increase plasma levels of these AChE inhibitors. Therefore, poor metabolizers, who lack CYP2D6 and CYP1A2, can be particularly predisposed to adverse drug interactions. In addition, a number of drugs that are substrates for cytochrome P450 enzyme system, including diazepam, warfarin and phenyloin are known to interact with these AChE inhibitors. Most common adverse effects reported in patients taking these AChE inhibitors include nausea, vomiting, diarrhea, and muscle cramps. Other adverse effects reported are liver disorder, arrhythmia, cardiovascular disorder, tachycardia, dizziness, abnormal gait, aggression, anxiety, anorexia, delirium, confusion, sleep disorder, cough, and dyspnea (Iimura et al. WO 2007052541).
Majority of the Alzheimer's patients are old people and are in the age group of 55 to 85 years. It has been observed that these patients have one or more health disorders other than Alzheimer's and they are most likely diabetes, cardiovascular problems (e.g., atherosclerosis, hypertension), chronic pain, asthma, and poor functioning of liver and kidney. The most concerned adverse effects of these AChE inhibitors are drug-drug interactions and cardiac liability. The CYP mediated metabolic pathways associated with these drugs are mainly responsible for the adverse effects. The majority of the drugs currently available for the treatment of diabetes, cardiovascular, asthma and chronic pain indications are metabolized by CYP enzymes. Therefore, Alzheimer's patients being treated with the AChE inhibitors are at greater risk for adverse side effects derived from drug-drug interactions. In some cases these adverse effects can become life threatening. Taken together, these clinical limitations point towards the need to develop safer therapeutic drugs for the treatment of Alzheimer's disease.
Therefore, development of a novel AChE inhibitors that preferably undergo non-CYP mediated metabolism in the body but display the same or improved therapeutic target activity as the currently available therapies would provide effective and safer medicines for the treatment of Alzheimer's disease.